This proposal describes a five-year training program for Dr. Sahar Nissim to achieve independence as an investigator in gastrointestinal disease. Dr. Nissim is an M.D.-Ph.D. physician scientist and prior trainee of the NIH-sponsored Medical Scientist Training Program, and has completed clinical training in Gastroenterology at the Brigham and Women's Hospital. He is now embarking on a research and career development program that will build on his rigorous Ph.D. training in developmental biology at the Harvard Medical School. Dr. Nissim will train under the co-mentorship of: Wolfram Goessling, M.D., Ph.D., Assistant Professor of Medicine at Brigham and Women's Hospital and Harvard Medical School who is an internationally-recognized leader in the study of endoderm development and liver disease using zebrafish; and, David Cohen, M.D., Ph.D, Director of Hepatology at the Brigham and Women's Hospital and Professor of Medicine at Harvard Medical School who is a world-renown expert in liver lipid metabolism with a long track record of successful mentorship. To further guide completion of his research and career goals, Dr. Nissim will meet regularly with a Scientific Advisory Committee comprised of Dr. Peter Banks, Professor Cliff Tabin, and Dr. Len Zon, who will provide expertise in pancreas disease, developmental biology, and zebrafish methodology, respectively. Dr. Nissim's career development plan incorporates coursework and collaboration at the Harvard Digestive Diseases Center and the Harvard Stem Cell Institute. He has detailed a clear timeline for publication of his work in peer-reviewed journals, presentations at national meetings, and development of independent research projects and funding. Dr. Nissim is focused on developing novel diagnostic and treatment strategies for pancreas diseases that he sees in the clinic, including pancreatitis and pancreatic cancer. Pancreatitis is the single most common gastrointestinal cause of hospital admission in the U.S., and pancreatic cancer remains one of the most lethal cancers. The objective of Dr. Nissim's research proposal is to investigate the function and therapeutic potential of Nuclear Receptor 5A2 (NR5A2), a gene recently implicated by a Genome-Wide Association Study but whose mechanism and impact on pancreas disease is not known. In preliminary work, Dr. Nissim has uncovered that NR5A2 plays a critical role in development of the pancreas and is required for normal differentiation of exocrine pancreas cells. Further, he has found that this developmental role may have relevance to adult disease, as NR5A2 expression is aberrantly lost in the context of pancreatitis and pancreatic cancer when exocrine cell differentiation is disrupted. To explore these findings further, the Specific Aims of this proposal are (1) to delineate the role and pathway interactions of NR5A2 in pancreas development, and (2) to test the functional impact of modulating NR5A2 in zebrafish models of pancreatitis and pancreatic cancer. As a nuclear receptor, NR5A2 would make an ideal pharmacologic target, and thus findings of this work have direct translational potential for management of patients with pancreas disease.